CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

629 HEPATITIS B VIRUS DNA LEVEL CHANGES IN HBEAG+ PREGNANT WOMEN RECEIVING TDF FOR PMTCT Nicole Ngo-Giang-Huong 1 , Nicolas Salvadori 1 , Woottichai Khamduang 2 , Tim R. Cressey 2 , Linda J. Harrison 3 , Luc Decker 1 , Camlin Tierney 3 , Jullapong Achalapong 4 , Trudy V. Murphy 5 , Noele Nelson 5 , George K. Siberry 6 , Raymond T. Chung 7 , Stanislas Pol 8 , Gonzague Jourdain 1 , for the iTAP study group 1 IRD, Chiang Mai, Thailand, 2 Chiang Mai University, Chiang Mai, Thailand, 3 Harvard University, Boston, MA, USA, 4 Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand, 5 CDC, Atlanta, GA, USA, 6 United States Agency for International Development, Arlingon, VA, USA, 7 Massachusetts General Hospital, Boston, MA, USA, 8 Cochin Hospital, Paris, France Background: High hepatitis B virus (HBV) DNA plasma levels and hepatitis B e antigen (HBeAg) carriage are the main risk factors of mother-to-child transmission (MTCT) of HBV. Antivirals can decrease HBV DNA levels and prevent HBV MTCT. Current guidelines recommend initiating antiviral prophylaxis when maternal HBV DNA level is above 200,000 IU/mL (5.3 log IU/mL); however, the optimal duration of treatment is unknown. Within a randomized trial, we assessed the changes of HBV DNA levels in HBeAg+ pregnant women receiving either tenofovir disoproxil fumarate (TDF) or placebo during pregnancy through the early postpartum period. Methods: HBV DNA was retrospectively quantified in HBsAg and HBeAg positive and HIV-negative pregnant women enrolled in a phase III, placebo- controlled, double-blind, randomized clinical trial assessing the efficacy and safety of TDF 300 mg once daily versus placebo from 28 weeks’ gestation through 2 months post-partum (NCT01745822). Samples were selected from all women assigned to the TDF arm and a randomly selected subset of women on placebo. HBV DNA plasma levels were measured at baseline (28 weeks), during the TDF course at weeks 32 and 36, delivery, and months 1 and 2 postpartum, and after TDF discontinuation at 3, 4, 6 and 12 months postpartum. HBV DNA levels were measured blind to the randomized arm using the RealTime HBV assay (Abbott Molecular Inc., IL, USA). Results: Of 331 women enrolled, 168 were randomized to TDF and 163 to placebo. Median HBV DNA levels in women on TDF decreased from 8.1 log IU/mL at baseline to 4.9 log IU/mL at 32 weeks, 4.2 at 36 weeks, 3.9 at delivery, 3.4 at 1 month and 3.3 at 2 months post-partum. After discontinuation of TDF, median HBV DNA level returned to baseline levels within one month. In the placebo arm median HBV DNA levels were unchanged during pregnancy and the postpartum period. In the TDF arm, 99 of 162 women (61%, exact 95% confidence interval [CI] 53% to 69%) had HBV DNA <200,000 IU/mL at 32 weeks, 133 of 158 (84%, CI 78% to 89%) at 36 weeks and 142 of 161 (88%, CI 82% to 93%) at delivery. Conclusion: In our study, more than 85% of pregnant women receiving TDF from 28 weeks’ gestation achieved HBV DNA levels below 200,000 IU/mL prior to delivery.

replication sites. Lipid coated P3TC nanocrystals (NP3TC) were prepared to further improve drug biodistribution and longevity. Methods: 3TC was modified and formulated into long acting lipid nanocrystals by high-pressure homogenization. Cellular drug uptake and retention was conducted in human monocyte-derived macrophages (MDM). To evaluate anti-HBV activity, TK-NOG mice were transplanted with human hepatocytes, and after confirmation of human albumin (Alb) concentration in peripheral blood (1.1 ± 0.2 mg/ml), animals were infected intravenously with patient- derived sera samples containing ~106 HBV DNA. Following confirmation of HBV DNA in peripheral blood, five animals were administered a single intramuscular dose of 75 mg/kg 3TC equivalents of NP3TC and controls (n=3) kept without drug. Levels of HBV DNA and HBsAg in plasma were monitored over the four- week experiment duration. At the end of the study, liver tissues were analyzed for histopathology, HBV DNA and RNA by ddPCR, and staining for human cells and viral proteins. Results: NP3TC nanocrystals had average particle sizes of 250-300 nm, polydispersity index of <0.2 and drug loading capacity of > 70%. NP3TC was readily taken up by MDM with sustained drug levels for up to 30 days; whereas native 3TC was eliminated within a day. In efficacy studies, single administration of NP3TC reduced HBV DNA from 4.38 ± 3.39 to 3.27 ± 2.75 log10 copies/ml and 3.38 ± 2.45 log10 copies/ml at two and four weeks post drug treatment, respectively, without loss of human cells or Alb levels. The results paralleled sustained drug levels in NP3TC treated animals. Conclusion: A long acting potent 3TC ProTide formulation was developed and preliminary studies showed sustained anti-HBV activity in humanized mice for weeks after single dosing. These results are promising for development of a long-acting potent formulation of 3TC for the treatment and prevention of HBV and HIV infections. 631 ANTI-INFLAMMATORY IL-10 IS INVERSELY RELATED TO CORONARY ATHEROSCLEROSIS IN HIV Lindsay T. Fourman 1 , Charles Saylor 1 , Lediya Cheru 1 , Kathleen V. Fitch 1 , Tricia H. Burdo 2 , Sara E. Looby 1 , Udo Hoffmann 1 , Michael T. Lu 1 , Janet Lo 1 1 Massachusetts General Hospital, Boston, MA, USA, 2 Temple University, Philadelphia, PA, USA Background: IL-10 is an anti-inflammatory cytokine secreted by monocytes, T cells, dendritic cells and other immune cells in response to systemic inflammation and is implicated in HIV viral persistence. However, IL-10 is thought to be protective against atherosclerosis, but this has not yet been studied in people with HIV (PWH). Therefore, we sought to understand the relationship of IL-10 with coronary atherosclerosis in PWH. Methods: Serum levels of the anti-inflammatory cytokine IL-10 were measured by ELISA (Invitrogen, MA) in a well-phenotyped observational study of men and women with HIV and matched HIV-negative controls, who were all asymptomatic and without known cardiovascular disease. Quantification of coronary plaque and plaque characteristics were obtained by coronary computed tomography angiography. Results: Among PWH, IL-10 inversely correlated with coronary segments with noncalcified plaque (rho=-0.24, p=0.004) and with coronary segments with any type of plaque (rho=-0.19, p=0.02), but not with segments with calcified plaque (rho=-0.009, p=0.92). Among HIV-negative controls, a similar directionality of relationships was seen for IL-10 and non-calcified plaque or any plaque, but the relationships were not statistically significant. Among PWH, no relationships were observed between IL-10 and several inflammatory markers known to be related to atherosclerosis in HIV (MCP-1, sCD163, sCD14, and IL-6). In logistic regression modeling adjusting for HIV RNA, CD4+ cells, total Framingham point score, BMI, race, MCP-1 and sCD163, lower IL-10 remained significantly related to presence of plaque (p=0.008). Conclusion: Higher IL-10 confers a lower risk of coronary plaque (and specifically non-calcified plaque) even when controlling for traditional cardiovascular risk factors, HIV RNA, CD4+ cells, and pro-inflammatory markers. The effects of IL-10 in HIV may be both protective and detrimental: while IL-10 may promote viral persistence, our study suggests that IL-10 may be involved in mitigating untoward coronary atherosclerosis.

Poster Abstracts

630 A LONG-ACTING 3TC NANOFORMULATION SUPPRESSES HBV REPLICATION IN HUMANIZED MICE

Nathan Smith , Weimin Wang, Edward Makarov, Yimin Sun, Catherine L. Gebhart, JoEllyn McMillan, Howard E. Gendelman, Larisa Y. Poluektova, Benson Edagwa University of Nebraska Medical Center, Omaha, NE, USA Background: Despite the success of existing antiretroviral therapy (ART) in controlling hepatitis B virus (HBV) infection, treatment requires life-long adherence to medicines. Compliance to ART can be compromised by frequency of dosing and adverse drug reactions. To this end, lamivudine (3TC), a nucleoside analog inhibitor of HBV and human immunodeficiency virus (HIV) infections, was modified into a lipophilic monophosphorylated prodrug (P3TC) to extend the apparent drug half-life, improve potency and facilitate access to viral

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